Epoxides, reaction with amide enolates

A direct application of the ring-opening reaction of an epoxide by a metal enolate amide for the synthesis of a complex molecule can be found in the synthesis of the trisubstituted cyclopentane core of brefeldin A (Scheme 8.35) [68a]. For this purpose, treatment of epoxy amide 137 with excess KH in THF gave a smooth cyclization to amide 138, which was subsequently converted into the natural product. No base/solvent combination that would effect cyclization of the corresponding aldehyde or ester could be found. 

S. K. Taylor, Reactions of Epoxides with Ester, Ketone and Amide Enolates , Tetrahedron 2000, 56, 1149-1163. 

Epoxides can also be used as substrates in pseudoephedrine amide enolate alkylation reactions, but react with opposite di-astereofacial selectivity (suggesting a change in mechanism, proposed to involve delivery of the epoxide electrophile by coordina-... 

Reactions of epoxides with ester, ketone and amide enolates 00T1149. b. Synthesis of Oxiranes. 

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

Perhaps the most interesting developments in the area of selective lithiations to appear this year have been concerned with the control of absolute stereochemistry. The application of chiral amide bases to the enantioselective deprotonation of epoxides was first described some years ago by Whitesell and co-workers, but this year several groups have reported on other aspects of these useful reaqents. Symmetrically substituted ketones (5 R=Me, CH2Ph) have been shown by Simpkins to undergo an enantioselective deprotonation under kinetically controlled conditions to give, after reaction with an electrophile (iodomethane, allyl bromide or acetic anhydride), optically active ketones (6) or enol acetates (7) (Scheme 2). The ability of a number of bases to discriminate between the two prochiral protons present in (5) were evaluated and the most effective of those studied was the camphor derivative (8) deprotonation of (5 R=Me) proceeded in 74% enantiomeric excess... 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Lithium amides derived from secondary amines like lithium diisopro-pylamide (1) appear to be strong enough bases to deprotonate epoxides, ketones, etc. However, when 1, which is a non-chiral base, deprotonates the non-chiral epoxide cyclohexene oxide (2), equal amounts of the two enantiomeric products (5)- and (/ )-cyclohex-2-enol (3) are formed in the abstraction of a proton from carbon 2 and 5, respectively, with accompanying opening of the epoxide ring (Scheme 1). Thus, none of the two enantiomeric products is formed in enantiomeric excess (ee), i.e., the reaction shows no stereoselectivity (Scheme 1). 

The alkylation of enolates 12 with alkyl halides under /A -topicity (meaning that (5)-12 is attacked from its Si-face) was plausibly explained by assuming that the Re-fAce is shielded by the (deprotonated) hydroxymethyl residue at the pyrrolidine skeleton. Remarkably, the opposite stereochemical outcome was observed in the reaction of enolate 12 with epoxides, as experienced by Askin and coworkers. In the combination of enolates derived from the enantiomeric amides (S)- and (1J)-11 with chiral epoxides, the configuration of stereogenic a-carbonyl center is widely determined by the chiral auxiliary [13]. 

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